BacNLR - Functional diversity of NLRs in multicellular bacteria

BacNLR是一个雄心勃勃的高风险/高增益项目，旨在揭示多细胞细菌中核苷酸结合寡聚化结构域样受体（nlr）的功能多样性，超越其在真核免疫中的既定作用。nlr存在于生命的所有领域，但它们在细菌中的作用却鲜为人知，因为它们的存在直到最近才被充分认识到。与大多数细菌不同，产生抗生素的多细胞链霉菌编码多个具有不同信号域的nlr，这表明这些蛋白质具有不同的功能。我们发现在链霉菌中，几种nlr样蛋白与抗生素的产生、发展有关，或与真核nlr具有同源性，可诱导程序性细胞死亡。因此，我们假设nlr信号在几个重要的细胞过程中起着至关重要的作用，迄今尚未被探索，包括抗生素产生、免疫和多细胞行为。为了揭示这些新的细胞作用，我开发了一种方法来综合激活链霉菌的NLR信号，克服了识别NLR激活的特定刺激的需要。这一突破使我们现在能够研究NLRs对调节抗生素生产的影响，并发现新的和可能意想不到的细胞作用。在BacNLR中，我们将使用生物信息学来识别细菌中NLR多样性的全谱；确定NLRs在多细胞链霉菌中的不同功能，并确定支撑这些功能的分子机制。BacNLR不仅将揭示NLR信号的新作用，还将揭示抗生素生产调控的基本新原理，为对抗耐药病原体的增加提供一种创新策略。所获得的知识将扩展我们目前关于nlr在所有王国的进化和功能多样性的模型，并作为细菌nlr信号通路工程的框架。

BacNLR is an ambitious high-risk/high-gain program to reveal the functional diversity of nucleotide-binding oligomerisation domain like receptors (NLRs) in multicellular bacteria that goes beyond their well-established role in eukaryotic immunity. NLRs are found in all domains of life, yet little is known about their role in bacteria because their existence has only recently been fully recognised.Unlike most bacteria, species of antibiotic-producing multicellular Streptomyces encode multiple NLRs with distinct signalling domains, suggesting that these proteins have diverse functions. We found that in Streptomyces several NLR-like proteins are linked to antibiotic production, development or share homology to eukaryotic NLRs shown to induce programmed cell death. We thereforehypothesise that NLR-signalling plays a crucial and so far unexplored role in several important cellular processes, including antibiotic production, immunity and multicellular behaviour.To reveal these novel cellular roles, I developed a method to synthetically activate NLR signalling in Streptomyces, overcoming the need to identify a specific stimulus for NLR activation. This breakthrough enables us now to study the impact of NLRs on regulating antibiotic production and to discover new and possibly unexpected cellular roles. In BacNLR, we will use bioinformatics to identify the full spectrum of NLR diversity in bacteria; determine the diverse functions of NLRs in multicellular Streptomyces and define the molecular mechanisms that underpin these functions.BacNLR will not only uncover new roles of NLR signalling but also reveal undamental new principles in the regulation of antibiotic production, providing an innovative strategy to combat the rise in drug-resistant pathogens. The gained knowledge will expand our current models about the evolution, and functional diversity of NLRs across all kingdoms and serve as a framework for engineeringNLR signalling pathways in bacteria.